Cancer immunotherapy involves the use of compositions and methods to elicit and enhance an individual's own immune system against cancerous cells, or infections that predispose to cancer. Cancer vaccines function by triggering the immune system to mount a response to an antigen (e.g., typically a protein, peptide, or carbohydrate) that is introduced into the body in a non-carcinogenic form and triggers the body to confer immunity or obtain a long-lived “memory” immune response. See, e.g., Kast, Peptide-Based Cancer Vaccines, Landes Bioscience (2000); Stem et al, Cancer Vaccines and Immunotherapy, Cambridge University Press (2000). Once the immune system response is established, exposure of the immune system to this antigen (e.g., in the form of a cancerous tumor) results in a rapid and robust immune response.
It is often necessary to enhance the immune response to the antigens present in a vaccine in order to stimulate the immune system to a sufficient extent to make a vaccine effective, i.e., to confer immunity. Many protein, peptide and carbohydrate antigens, administered alone, do not generate a sufficient response to confer immunity. The reasons for this may be that the antigens recognized by cancer reactive immune responses originate from proteins that are expressed in normal tissue of the same histological type as the cancer, such that immunologic tolerance may prevent effective immune responses to the antigens. Such antigens need to be presented to the immune system in such a way that they will generate an immune response. To this end, adjuvants have been devised which immobilize antigens and enhance the immune response. The best known adjuvant, Freund's complete adjuvant, consists of a mixture of mycobacteria in an oil/water emulsion. Freund's adjuvant works (i) by enhancing cell and humoral-mediated immunity and (ii) by blocking rapid dispersal of the antigen challenge (the depot effect). Freund's adjuvant is used primarily with experimental therapies to help stimulate the immune system in animals, and in humans the mycobacterial preparation Bacille Calmette-Guérin (BCG), is an immunotherapy approved as a treatment for bladder cancer.
Another molecule that has been shown to have immunostimulatory or adjuvant activity is endotoxin, also known as lipopolysaccharide (LPS). LPS is also a model adjuvant that can overcome tolerance to self antigens. Waldner, et al., J. Clin. Invest., (2004); 113 990-997. While LPS is too toxic to be a viable adjuvant, molecules that are structurally related to endotoxin, such as monophosphoryl lipid A (“MPL”), are being tested as adjuvants in clinical trials. The only FDA-approved adjuvant for use in humans are aluminum salts, alum.
There is a need in the art for safe and effective compositions that can stimulate the immune system as a cancer immunotherapeutic. The invention is directed to this, as well as other, important ends.